Sickle cell disease and 2-thalassemia continue to cause severe morbidity and early death. While supportive care for patients has improved, there is still no widely available therapy that targets the underlying molecular causes of these diseases. Strategies to increase levels of fetal hemoglobin (HbF) have the potential to inhibit sickle hemoglobin polymerization and to mitigate the globin chain imbalance of 2-thalassemia, thus improving the lives of people with these diseases. The long-term goal of our research is to develop improved strategies for the pharmacologic induction of fetal hemoglobin (PIFH) that will have the efficacy, safety, ease of use and affordability that will make them applicable to people with 2-hemoglobinopathies worldwide. Approaches to achieve this goal include characterization of the molecular mechanisms underlying PIFH and the identification of novel molecular targets and improved pharmacologic strategies for PIFH. This project focuses on understanding the role of the Integrated Stress Response (ISR) cell signaling pathway in PIFH and how stress signaling may cause preferential translation of 3-globin mRNA. This will be accomplished through two research aims: Aim I - To characterize the mechanism by which ISR signaling mediates pharmacologic induction of HbF. Aim 2- To test the hypothesis that 3-globin mRNA is capable of cap-independent translation. Continued progress in hemoglobinopathy and related blood disorders research is dependent on the development of highly skilled and motivated young investigators dedicated to translational hematology research. An additional objective of this project is to enhance physician-scientist career development. In addition to a rigorous medical school curriculum and the research program described above, this will include advanced classes in experimental therapeutics and clinical investigation, a structured mentoring program, and a series of experiences specifically designed as an introduction to clinical hematology and hematology-related translational research. PUBLIC HEALTH RELEVANCE: While pharmacologic induction of fetal hemoglobin has proven ability to improve the lives of people with sickle cell disease and 2-thalassemia, none of the currently available drugs offer the ideal combination of safety, efficacy, ease of use, and affordability that would make them applicable to most patients. This project will investigate a novel mechanism of fetal hemoglobin induction in an effort to identify improved strategies for increasing fetal hemoglobin levels in patients with 2-hemoglobinopathies.